Method for the preparation of 2-halo-2&#39;-deoxyadenosine compounds from 2&#39;-deoxyguanosine

ABSTRACT

The present invention is a method for preparing 2-halo-6-aminopurines, and more specifically for preparing the clinical agent cladribine (2-chloro-2′-deoxyadenosine, CldAdo, 4), a drug of choice against hairy-cell leukemia and other neoplasms, from 2-amino-6-oxopurines, which are readily obtained from the naturally occurring compound 2′-deoxyguanosine. According to the methods of the present invention, the 6-oxo group of a protected 2′-deoxyguanosine (1) is converted to a 6-(substituted oxy) leaving group, or alternatively to a 6-chloro leaving group, the 2-amino group is replaced with a 2-chloro group, the 6-(substituted oxy) leaving group, or alternatively the 6-chloro leaving group, is replaced with a 6-amino group or, alternatively, a 2,6-dichloro substituted compound is selectively replaced with a 6-amino group, and the protecting groups are removed.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.10/529,106, which is a 371 national phase of PCT/US2003/030386, filedSep. 25, 2003, and claims the benefit under 35 U.S.C. § 119(e) of U.S.Provisional Application No. 60/413,915, filed Sep. 25, 2002, and U.S.Provisional Application No. 60/416,329, filed Oct. 4, 2002.

BACKGROUND Field of the Invention

The present invention is directed to processes for preparing2-halo-6-aminopurines, and more particularly to a process for preparing2-chloro-2′-deoxyadenosine.

The lymphoselective toxicity of 2-chloro-2′-deoxyadenosine (CldAdo,cladribine) and its potential as a chemotherapeutic agent againstlymphoid neoplasms were reported by Carson et al.¹ This potent,deaminase-resistant analogue of 2′-deoxyadenosine (dAdo) is currentlythe drug of choice for hairy-cell leukemia.^(2,3) It also hassignificant activity against chronic lymphocytic leukemia,^(4,5)indolent non-Hodgkin's lymphoma,⁶ and Waldenström's macroglobulinemia.⁷Investigations with cladribine treatment of multiple sclerosis,⁸systemic lupus erythematosis-associated glomerulonephritis,⁹ and otherrheumatoid and immune disorders are in progress. Cladribine is anucleoside prodrug, which is phosphorylated by deoxycytidine kinase toCldAMP, and then sequentially to CldADP and the active CldATP.^(1a,10a)Cladribine also is a good substrate for mitochondrial 2′-deoxyguanosine(dGuo) kinase,¹⁰ and induction of programmed cell death by directeffects on mitochondria has been implicated in its potent activityagainst indolent lymphoid malignancies (via apoptosis) as well as inproliferating cells.^(11,12)

Various methodologies have been published for the production ofCladribine. Venner reported Fischer-Helferich syntheses of naturallyoccurring 2′-deoxynucleosides in 1960,¹³ and employed2-chloro-2′-deoxyadenosine as an intermediate for 2′-deoxy(guanosine andinosine). Ikehara and Tada also synthesized dAdo with CldAdo as anintermediate [obtained by desulfurization of8,2′-anhydro-9-(β-D-arabinofuranosyl)-2-chloro-8-thioadenine].¹⁴

Syntheses of CldAdo as a target compound have exploited the greaterreactivity of leaving groups at C6 relative to those at C2 of the purinering in S_(N)Ar displacement reactions. Robins and Robins¹⁵ employedfusion coupling of 2,6-dichloropurine with1,3,5-tri-O-acetyl-2-deoxy-α-D-ribofuranose. The9-(3,5-di-O-acetyl-2-deoxy-α-D-erythro-pentofuranosyl)-2,6-dichloropurineanomer was obtained by fractional crystallization. Selective ammonolysisat C6 and accompanying deprotection gave6-amino-2-chloro-9-(2-deoxy-α-D-erythro-pentofuranosyl)purine. Thepharmacologically active β-anomer (cladribine) was prepared by ananalogous coupling, chromatographic separation of anomers, andammonolysis.¹⁶

Stereoselective glycosylation of sodium salts of halopurines andanalogues with 2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranosylchloride gave β-nucleoside anomers via predominant Waldeninversion,^(17, 18) and ammonolysis/deprotection gave CldAdo.¹⁹ Althoughthe sodium salt glycosylation usually gave good anomericstereoselectivity, minor quantities of a anomers and >10% of N7regioisomers were usually formed.^(20,21) This requires separations andresults in diminished yields of the desired N9 product. Carson et al.¹had reported an enzymatic transfer of the 2-deoxy sugar from thymidineto 2-chloroadenine (ClAde). Holy and coworkers noted that cells of astrain of Escherichia coli performed glycosyl transfer from2′-deoxyuridine to 2-chloro-6-[(dimethylaminomethylene)amino]purine togive a derivative of CldAdo.²² Very recently Barai, Mikhailopulo, andcoworkers²³ described an E. coli-mediated glycosyl transfer synthesis of2,6-diamino-9-(3-deoxy-β-D-erythro-pentofuranosyl)purine,²⁴ and itsenzymatic deamination to 3′-deoxyguanosine.²⁴ They reported glycosyltransfer from 2′-deoxyguanosine to ClAde, and claimed a yield of 81% ofCldAdo (based on ClAde).²³ However, a 3:1 ratio of dGuo/ClAde wasemployed, so the yield of CldAdo was <27% based on dGuo.

Sampath et al. have recently shown (U.S. Pat. No. 6,596,858 B2) a methodfor making 2-chloro-2′-deoxyadenosine compounds, using2-amino-2′-deoxyadenosine as a starting compound, but beginning with aninitial diazotization/chloro-dediazoniation reaction on the unprotectednucleoside to replace the 2-amino group with a 2-chloro group. Thismethod, however, creates various impurities, which requires extensivepurification procedures, and results in an overall yield of only 27%.

Accordingly, there is a significant need to produce CldAdo using methodsthat result in a higher yield, are more cost effective, and result in amore purified form.

BRIEF SUMMARY

The present invention is a method for producing2-chloro-2′-deoxyadenosine (CldAdo) comprising the steps of: (a)converting the 6-oxo group of a compound having the formula (1) whereinR is a protecting group, into a 6-leaving group having sufficientreactivity for an S_(N)Ar displacement reaction; (b) replacing the2-amino group with a 2-chloro group in adiazotization/chloro-dediazoniation reaction; (c) replacing the6-leaving group with a 6-amino group; and (d) removing the R protectinggroups, to produce 2-chloro-2′-deoxyadenosine.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the chemical synthesis of 2-chloro-2′-deoxyadenosine fromprotected forms of naturally occurring 2′-deoxyguanosine.

FIG. 2 shows the diazotization/halo-dediazoniation conversion reactionfrom a 2-aminopurine nucleoside to a 2-halopurine nucleoside.

DETAILED DESCRIPTION OF THE DRAWINGS AND THE PRESENTLY PREFERREDEMBODIMENTS

In accordance with the present invention, synthesis of regio- andstereochemically pure 2-chloro-2′-deoxyadenosine (Cladrabine, orCldAdo), which avoids separation of mixtures with fusion and sodium saltglycosylation procedures, is accomplished by transformation of thenaturally occurring nucleoside 2′-deoxyguanosine (dGuo) as the startingcompound.²⁴ Methods for producing CldAdo from 2′-deoxyguanosine (dGuo)according to the present invention begin with protected forms of dGuoincluding, but not restricted to, acyl, silyl, amide, and otherderivatives useful in the field of nucleoside/nucleotide/nucleic acidchemistry and protection strategies. Methods for obtaining protectedforms of dGuo are well-known in the art.^(25,26,27,28,29,30) Thepreferred starting products for efficient synthesis of CldAdo aredefined by the following chemical structure:

where R is any suitable protecting group, and preferably R is Ac or Bz.

In order to obtain the desired CldAdo compounds, protected dGuoderivatives are treated with combinations of chemicals that effectfunctionalization at the C6 position to give groups that can bereplaced, followed by transformation of the 2-amino function to a2-chloro group, followed by replacement of the 6-functional group togive a 6-amino group (or a 6-substituent that can be converted into a6-amino group, followed by conversion to the 6-amino group), andconcomitant or subsequent deprotection of the resulting6-amino-2-chloropurine derivative to give CldAdo. For example, fromdGuo, CldAdo (4) (FIG. 1) is synthesized by converting the 6-oxofunction into appropriate 6-(substituted oxy) leaving groups that can bereplaced without protection of the 2-amino moiety, transformation of the2-amino function to a 2-chloro functional group bydiazotization/chloro-dediazoniation of the 2-amino function, andselective C6 ammonolysis of the 2-chloro-6-(substituted)purinederivatives, with accompanying sugar deprotection. This routeadvantageously provides retention of both β-anomeric stereochemistry andN9 isomeric purity.

Functionalization of the 6-oxo group is accomplished by converting,without protection of the 2-amino moiety, the 6-oxo group to a6-(substituted oxy) leaving group having greater reactivity than the2-chloro group in a S_(N)Ar displacement reaction. Two preferred methodsfor functionalization at the C6-oxy group include alkyl- orarylsulfonylation of the C6-oxy group and chlorodeoxygenation at C6.

Alkyl- or arylsulfonylation of the C6-oxy group can be accomplished bytreating protected dGuo derivatives with (alkyl or any substituted alkylor cycloalkyl)sulfonyl, phosphoryl or phosphonyl reagents or (aryl orany substituted aryl)sulfonyl, phosphoryl or phosphonyl reagents, whichinclude, for example, sulfonyl compounds having the formula R′SO₂-X,where X is a halogen (such as chloride), imidazolide, triazolide ortetrazolide and R′ is alkyl, substituted alkyl (including but notlimited to fluoroalkyl), cycloalkyl, aryl, or substituted aryl, toconvert the 6-oxo group to a 6-O-(alkyl, substituted alkyl, cycloalkyl,aryl or substituted aryl)sulfonyl group. In preferred embodiments,3′,5′-di-O-(acetyl or benzoyl)-2′-deoxyguanosine (1) is treated with(2,4,6-triisopropyl or 4-methyl)benzenesulfonyl chloride, to give highyields of the 6-O-arylsulfonyl derivatives 2 or 2′b. In other preferredembodiments, 1 is treated with TiPBS-Cl, which gives the 6-O-TiPBSderivative 2a or 2b, or TsCl, which gives the 6-O-Ts derivative 2′b.

Several acyl-protected 6-O-sulfonyl derivatives of dGuo that can beutilized are known in the art.^(28,29,30) Treatment of3′,5′-di-O-acetyl-2′-deoxyguanosine³¹ (1a) or its 3′,5′-di-O-benzoylanalogue 1b³¹ with TiPBS-Cl/Et₃N/DMAP/CHCl₃ by the general method ofHata et al.²⁹ gave the 6-O-TiPBS derivatives 2a³² (91%) or 2b (86%),respectively. Similar treatment of 1b with TsCl/Et₃N/DMAP/CHCl₃ gave the6-O-Ts derivative 2′b (89%). Efficient displacement of sulfonate from C6in following steps requires a sterically hindered arylsulfonylderivative. A more economical 6-O-tosyl derivative gave lower yields atthe final stage owing to attack of ammonia at both sulfonyl sulfur andC6 (3′b gave 4 in 43% yield). By contrast, ammonolysis of the 6-O-TiPBSderivatives proceeded efficiently at C6 with minimal attack at thehindered sulfur atom. Both types of such arylsulfonate derivatives, andespecially the 6-O-Ts, underwent increased nucleophilic attack at sulfurwith lower temperatures (−20 to 0° C.) to give 6-oxopurine derivatives,resulting in a lower yield. However, treatment of the 6-O-TiPBScompounds with NH₃/MeOH/CH₂Cl₂ in a pressure tube at 80° C. stronglyfavored nucleophilic attack at C6 to give good yields of CldAdo (4).

Alternatively, the 6-oxo group can be replaced by a 6-chloro leavinggroup by chlorodeoxygenation at C6. Chlorine is the most frequently usedleaving group at C6 of purine nucleosides. Methods for producing CldAdofrom dGuo begin with protected forms of dGuo described above and involvetreatment of such derivatives with combinations of chemicals thatconvert the 6-oxo function into a 6-chloro group that can be replaced onthe resulting 2-amino-6-chloropurine derivative. Deoxychlorination at C6of 1 results in excellent yields of the 2-amino-6-chloropurinederivatives 5. In preferred embodiments, protected dGuo derivatives aretreated with phosphoryl chloride, a source of soluble chloride, anorganic base, and acetonitrile or other compatible solvent, to convertthe 6-oxo function into a 6-chloro group.

Original studies on deoxychlorination of guanosine³³ (Guo) and dGuo³⁴derivatives with POCl₃ gave moderate (Guo) to poor (dGuo) yields of2-amino-6-chloropurine products, and improved procedures have beenreported.^(26a,35,36) The acid-labile 2′-deoxy derivatives 1 weredeoxychlorinated with POCl₃/N,N-dimethylaniline/BTEA-Cl/MeCN/Δ,^(26a,36)and 6-chloro derivatives 5a (90%) and 5b (85%) were obtained in highyields under carefully controlled conditions.

Following the step of converting the 6-oxo group to a 6-(substitutedoxy) leaving group, the 2-amino group is replaced with a 2-chloro groupby a diazotization/halo-dediazoniation reaction. Improved methods aredisclosed for replacement of an amino group on purine nucleosidederivatives with chlorine, bromine, or iodine under non-aqueousconditions by diazotization/halo-dediazoniation methods.²⁷ These milddiazotization/halo-dediazoniation methods are applicable at C6 of dAdoderivatives as well as at C2 of 2-amino-6-chloropurine nucleosides. Inaccordance with the present invention, CldAdo is produced from dGuo bytreatment of protected forms of dGuo that contain a respective6-O-(alkyl, cycloalkyl, or aryl)sulfonyl group with reagents that effectdiazotization/chloro-dediazoniation at C2 to give a 2-chloro group.CldAdo is also produced by treating protected 2-amino-6-chloropurinederivatives with reagents that effectdiazotization/chloro-dediazoniation at C2 to give respective2,6-dichloropurine derivatives.

Reagents that effect diazotization/chloro-dediazoniation at C2 to give a2-chloro group include a halide source (such as metal chlorides, metalchloride salts, acyl chlorides, sulfonyl chlorides, and silyl chlorides,alkyl and aryl substituted ammonium chloride salts, including but notlimited to tetraalkyl and aryl ammonium chloride salts) and a nitritesource (such as metal nitrites, metal nitrite salts, organic nitrites,such as tert-butyl nitrite, pentyl nitrite, and isoamyl nitrite, andcomplex quaternary ammonium nitrites, such as benzyltriethylammoniumnitrite).

In preferred embodiments of the present invention, CldAdo is synthesizedby employing acetyl chloride and benzyltriethylammonium nitrite(BTEA-NO₂)-mediated diazotization/chloro-dediazoniation of6-O-(2,4,6-triisopropylbenzenesulfonyl) (TiPBS) or 6-chloro derivativesthat are readily obtained from dGuo. Non-aqueousdiazotization/chloro-dediazoniation (acetylchloride/benzyltriethylammonium nitrite) of 2, 2′b, or 5 gave the2-chloropurine derivatives 3, 3′b, or 6, respectively. This newprocedure for non-aqueous diazotization/chloro-dediazoniation²⁷(AcCl/BTEA-NO₂/CH₂Cl₂/−5 to 0° C.) worked well for replacement of the2-amino group of 2, 2′b, and 5 with chlorine to give 3a (89%), 3b (90%),3′b (87%), 6a (95%), and 6b (91%).

Efficient diazotization/chloro-dediazoniation of9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2-amino-6-chloropurine^(26,33)(7) (FIG. 2) was effected with TMS-C1 (9 equivalents) andbenzyltriethylammonium nitrite (BETA-NO₂) (3 equivalents) in CH₂Cl₂ atambient temperature. The process was rapid (<30 min), and the desired9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloropurine^(27,37) (8)(83%, without chromatography) was obtained as a white crystalline solid.Comparable yields were obtained at 0° C. TMS-Cl (3.5 equivalents) andBTEA-NO₂ (1.5 equivalents) with powdered NaNO₂ (5 equivalents) gave 8(86%) within 1 hr. By contrast, an alternative method for non-aqueousdiazotization/chloro-dediazoniation of 7 employed Cl₂/TBN/CuCl in astrongly exothermic reaction, and removal of colloidal material byfiltration was required prior to crystallization of 7.³⁵

Compound 7 underwent efficient diazotization/bromo-dediazoniation withTMS-Br and tert-butyl nitrite (TBN). Competing redox interactionsbetween nitrite anion and TMS-Br precluded the use of NaNO₂. The2-bromo-6-chloropurine nucleoside 3^(27,37) (85%, withoutchromatography) was obtained as a crystalline solid with TMS-Br (9equivalents)/TBN (20 equivalents)/CH₂Br₂/ambient temperature within 1 h.

NOCl/CH₂Cl₂ or NOBr/CH₂Br₂ is presumed to be generated from (Me₃SiX orAcCl) and (TBN or BTEA-NO₂). These procedures provide efficientdiazotization/halo-dediazoniation of protected (2 or 6)-aminopurinenucleosides as well as the acid-sensitive 2′-deoxynucleosides. Thereactions are cost-effective and proceed at or below ambient temperaturewith convenient reagents and standard laboratory equipment andconditions.

Following replacement of the 2-amino group with a 2-chloro group, theprotected forms of dGuo that contain a respective 6-O-(alkyl,cycloalkyl, or aryl)sulfonyl or phosphoryl group and a 2-chloro group isreacted with chemicals that cause replacement of the 6-O-(alkyl,cycloalkyl, or aryl) sulfonyl or phorphoryl group to give a 6-aminogroup (or a substituent that can be converted into a 6-amino group,resulting in overall conversion of the substituent into a 6-amino group)of a resulting 6-amino-2-chloropurine derivative. In preferredembodiments, the 6-leaving group is replaced with a 6-amino group byreacting the product of step (b) with a nitrogen source capable of beingconverted to an amino group in a solvent compatible with the nitrogensource to replace the 6-leaving group with a 6-amino group by selectiveammonolysis of the 6-leaving group. The nitrogen source is selected fromthe group consisting of ammonia, azides, hydrazines, benzylic amines, orcompatible ammonium salts. The solvent may be any solvent that iscompatible with the nitrogen source, such as methanol, ethanol, higheralcohols, or aprotic solvents, such as 1,2-dimethoxyethane,tetrahydrofuran, or DMF.

In other preferred embodiments, the respective 6-O-(alkyl, cycloalkyl,or aryl)sulfonyl leaving group is reacted with ammonia in a compatibleaprotic solvent to give a 6-amino-2-chloropurine derivative, followed bydeprotection (if necessary) to give CldAdo. In a more preferredembodiment, a 9-(3,5-di-O-acyl-β-D-erythro-pentofuranosyl-6-O-(alkyl,cycloalkyl, or aryl)sulfonyl-2-chloropurine is treated with ammonia inmethanol or other compatible solvent to give CldAdo.

Further, protected derivatives of 2,6-dichloropurine are treated withreagents that cause selective replacement of the 6-chloro group to givea 6-amino group (or a substituent that can be converted into a 6-aminogroup, followed by conversion of the substituent into a 6-amino group)of a resulting 6-amino-2-chloropurine derivative. In a more preferredembodiment,9-(3,5-di-O-acyl-β-D-erythro-pentofuranosyl)-2,6-dichloropurine istreated with ammonia in methanol or other compatible solvent to giveCldAdo.

Selective ammonolysis at C6 (arylsulfonate with 3 or chloride with 6)and accompanying deprotection of the sugar moiety gave CldAdo (4)(64-75% overall from 1). Specifically, displacements of the hinderedarylsulfonate (from 3) or chloride (from 6) at C6 with accompanyingcleavage of the sugar esters were effected at 80° C. withNH₃/MeOH/CH₂Cl₂. Cladribine (4) was obtained in high yields from 3a(81%), 3b (83%), 6a (87%), and 6b (94%), but only in moderate yield fromthe 6-O-tosyl derivative 3′b (43%).

The R protecting groups are removed by deacylation using a basic reagentwell known in the art in a solvent compatible with the basic reagent, toremove the R protecting groups and produce 2-chloro-2′-deoxyadenosine.The basic reagent is selected from the group consisting of ammonia,metal alkoxides, metal hydroxides, and metal carbonates. The solvent maybe any solvent that is compatible with the basic reagent, such asmethanol, ethanol, 1,2-dimethoxyethane/H₂O, or tetrahydrofuran/H₂O.

It is to be noted that removal of the R protecting groups may occurconcomitantly with or subsequent to the replacement of the6-(substituted oxy) leaving group with a 6-amino group by ammonolysis.Both steps of replacement of the 6-(substituted oxy) leaving group witha 6-amino group and removal of the R protecting groups is accomplishedby use of a nitrogen source in a solvent compatible with the nitrogensource. Where the nitrogen source is ammonia in a protic solvent, suchas methanol or ethanol, both steps proceed simultaneously. However,where the nitrogen source is anhydrous ammonia in a dry solvent, such as1,2-dimethoxyethane, or tetrahydrofuran, only the step of replacement ofthe 6-(substituted oxy) leaving group with a 6-amino group proceeds. Inthis case, it is necessary and sometimes desirable to remove the Rprotecting groups in a separate step.

In the most preferred embodiments of the present invention, synthesis ofthe clinical drug cladribine (2-chloro-2′-deoxyadenosine, CldAdo, 4) wasaccomplished in three steps from the readily available3′,5′-di-O-acetyl-2′-deoxyguanosine (1a) or its dibenzoyl analogue 1b.Replacement of the 2-amino group proceeded in high yields bydiazotization/chloro-dediazoniation with AcCl/BTEA-NO₂. Selectiveammonolysis of 3a and 3b (6-OTiPBS) or 6 (6-Cl), with accompanyingdeacylation, gave 4 (64-75% overall). Ammonolysis of 3′b (6-OTs) wasproblematic and gave 4 in poor overall yield (33%). Routes that employeddeoxychlorination of 1 were ˜10% more efficient overall than those whichinvolved 6-O-TiPBS intermediates.

EXAMPLES

Melting points for 4 were determined with a hot-stage apparatus. UVspectra were recorded with solutions in MeOH. ¹H NMR spectra wererecorded at 300 MHz with solutions in CDCl₃ unless otherwise indicated.“Apparent” peak shapes are in quotation marks when first-order splittingshould be more complex or when peaks were poorly resolved. Mass spectra(MS) were determined with FAB (glycerol) unless otherwise indicated.Chemicals and solvents were of reagent quality. CH₂Cl₂ and MeCN weredried by reflux over and distillation from CaH₂. CHCl₃ was dried overP₂O₅ and distilled. AcCl, POCl₃, and N,N-dimethylaniline were freshlydistilled before use. Benzyltriethylammonium nitrite (BTEA-NO₂) wasprepared from BTEA-Cl by ion exchange [Dowex 1×2 (NO₂ ⁻)]. Columnchromatography (silica gel, 230-400 mesh) was performed withCH₂Cl₂/MeOH. Compounds 1a and 1b were prepared as described.³¹

Method 1 (nucleoside/TiPBS-Cl/DMAP/Et₃N/CHCl₃) is described for 1a→2a,method 2 (nucleoside/AcCl/BTEA-NO₂/CH₂Cl₂) for 2a→3a, method 3(nucleoside/N,N-dimethylaniline/POCl₃/BTEA-Cl/MeCN) for 1a→5a, andmethod 4 (nucleoside/NH₃/MeOH/Δ) for 3a→4. Analogous reactions withequivalent molar proportions of other nucleosides gave the indicatedproducts and quantities.

Example 1

Preparation of9-(3,5-Di-O-acetyl-2-deoxy-β-D-erythro-pentofuranosyl)-2-amino-6-O-(2,4,6-triisopropylbenzenesulfonyl)purine(2a). Method 1. Et₃N (1.25 mL, 910 mg, 9.0 mmol) was added to a stirredsolution of 1a (1.67 g, 4.8 mmol), TiPBS-Cl (2.73 g, 9.0 mmol), and DMAP(72 mg, 0.6 mmol) in dried CHCl₃ (70 mL) under N₂. Stirring wascontinued for 24 h, and volatiles were evaporated. The orange residuewas chromotographed (CH₂Cl₂/MeOH) give 2a³² (2.67 g, 91%) as a slightlyyellow foam with UV max 238, 291 nm, min 264 nm; ¹H NMR (500 MHz) δ1.26-1.32 (m, 18H), 2.08 (s, 3H), 2.14 (s, 3H), 2.54 (ddd, J=4.7, 9.0,14.0 Hz, 1H), 2.91-2.99 (m, 2H), 4.22-4.37 (m, 3H), 4.43-4.47 (m, 2H),4.97 (br s, 2H), 5.41-5.42 (“d”, 1H), 6.26-6.29 (m, 1H), 7.21 (s, 2H),7.84 (s, 1H); LRMS m/z 618 (MH⁺[C₂₉H₄₀N₅O₈S]=618); HRMS m/z 640.2413(MNa⁺[C₂₉H₃₉N₅O₈SNa]=640.2417).

Example 2

Preparation of2-Amino-9-(3,5-di-O-benzoyl-2-deoxy-β-D-erythro-pentofuranosyl)-6-O-(2,4,6-triisopropylbenzenesulfonyl)purine (2b). Treatment of 1b (950 mg, 2.0 mmol) by method 1 gave 2b(1.27 g, 86%) as a white solid foam with UV max 289 nm, min 264 nm; ¹HNMR δ 1.29-1.32 (m, 18H), 2.76 (ddd, J=2.1, 6.0, 14.3 Hz, 1H), 2.96(“quint”, J=6.8 Hz, 1H), 3.15-3.25 (m, 1H), 4.34 (“quint”, J=6.8 Hz,2H), 4.65-4.74 (m, 2H), 4.85-4.90 (m, 1H), 5.00 (br s, 2H), 5.84-5.86(“d”, 1H), 6.38-6.43 (m, 1H), 7.30 (s, 2H), 7.44-7.55 (m, 4H), 7.58-7.69(m, 2H), 7.85 (s, 1H), 8.04 (d, J=7.1 Hz, 2H), 8.11 (d, J=7.1 Hz, 2H);LRMS m/z 742 (MH⁺[C₃₉H₄₄N₅O₈S]=742), 764 (MNa⁺[C₃₉H₄₃N₅O₈SNa]=764); HRMSm/z 764.2730 (MNa⁺ [C₃₉H₄₃N₅O₈SNa]=764.2730).

Example 3

Preparation of2-Amino-9-(3,5-di-O-benzoyl-2-deoxy-β-D-erythro-pentofuranosyl)-6-O-(4-methylbenzenesulfonyl)purine(2′b). Et₃N (700 μL, 506 mg, 5.0 mmol) was added to a stirred solutionof 1b (1.43 g, 3.0 mmol), TsCl (858 mg, 4.5 mmol), and DMAP (36 mg, 0.3mmol) in dried CHCl₃ (45 mL) under N₂. Stirring was continued for 15 h,and volatiles were evaporated. The slightly yellow residue waschromotographed (CH₂Cl₂/MeOH) to give 2′b (1.68 g, 89%) as a white solidfoam with UV max 300 nm; ¹H NMR (DMSO-d₆) δ 2.43 (s, 3H), 2.73 (ddd,J=2.1, 8.4, 14.4 Hz, 1H), 3.17-3.27 (“quint”, J=7.2 Hz, 1H), 4.52-4.65(m, 3H), 5.76-5.78 (“d”, 1H), 6.37-6.41 (m, 1H), 6.95 (br s, 2H),7.47-7.73 (m, 8H), 7.95 (d, J=7.8 Hz, 2H), 8.03-8.11 (m, 4H), 8.30 (s,1H); LRMS m/z 630 (MH⁺[C₃₁ H₂₈N₅O₈S]=630), m/z 652(MNa⁺[C₃₁H₂₇N₅O₈SNa]=652); HRMS m/z 652.1467(MNa⁺[C₃₁H₂₇N₅O₈SNa]=652.1478).

Example 4

Preparation of9-(3,5-Di-O-acetyl-2-deoxy-β-D-erythro-pentofuranosyl)-2-chloro-6-O-(2,4,6-triisopropylbenzenesulfonyl)purine(3a). Method 2. A solution of AcCl (200 μL, 220 mg, 2.8 mmol) in driedCH₂Cl₂ (12 mL) under N₂ was chilled in a NaCl/ice/H₂O bath (−5 to 0° C.)for 15 min. BTEA-NO₂ (520 mg, 2.2 mmol) was dissolved in dried CH₂Cl₂ (8mL) and this solution was immediately added dropwise to the cold,stirred solution of AcCl/CH₂Cl₂. A solution of 2a (288 mg, 0.5 mmol) indried CH₂Cl₂ (5 mL) was then added dropwise to the cold solution, andstirring was continued for 5 min (TLC, CH₂Cl₂/MeOH, 95:5, showedcomplete conversion of 2a into a single product). The reaction mixturewas added dropwise at a rapid rate to a cold (ice/H₂O bath), vigorouslystirred mixture of saturated NaHCO₃/H₂O (100 mL)//CH₂Cl₂ (100 mL). Thelayers were separated, and the organic phase was washed with cold (0°C.) H₂O (2×100 mL) and dried (MgSO₄) for 1 h. Volatiles were evaporated,and the residue was chromatographed (CH₂Cl₂/MeOH) to give 3a (267 mg,89%) as a white solid foam with UV max 240, 266 nm, min 255 nm; ¹H NMR(500 MHz) δ 1.24-1.31 (m, 18H), 2.08 (s, 3H), 2.13 (s, 3H), 2.67 (ddd,J=2.5, 7.0, 15.5 Hz, 1H), 2.76-2.81 (m, 1H), 2.90-2.96 (“quint”, J=7.0Hz, 1H), 4.28-4.33 (“quint”, J=7.0 Hz, 2H), 4.35-4.39 (m, 3H), 5.38-5.39(“d”, 1H), 6.42-6.45 (m, 1H), 7.22 (s, 2H), 8.23 (s, 1H); LRMS m/z 637(MH⁺ [C₂₉H₃₈ClN₄O₈S]=637); HRMS m/z 659.1902 (MNa⁺[C₂₉H₃₇ClN₄O₈SNa]=659.1918).

Example 5

Preparation of9-(3,5-Di-O-benzoyl-2-deoxy-β-D-erythro-pentofuranosyl)-2-chloro-6-O-(2,4,6-triisopropylbenzenesulfonyl)purine(3b). Treatment 2b (1.20 g, 1.6 mmol) by method 2 gave 3b (1.10 g, 90%)as a yellow solid foam with UV max 230, 266 nm, min 255 nm; ¹H NMR δ1.22-1.34 (m, 18H), 2.92-3.00 (m, 3H), 4.30-4.34 (m, 2H), 4.68-4.77 (m,3H), 5.80-5.82 (“d”, 1H), 6.54-6.57 (m, 1H), 7.42-7.64 (m, 8H), 8.00 (d,J=8.4 Hz, 2H), 8.10 (d, J=8.4 Hz, 2H), 8.26 (s, 1H); HRMS m/z 783.2224(MNa⁺ [C₃₉H₄₁ClN₄O₈SNa]=783.2231).

Example 6

Preparation of9-(3,5-Di-O-benzoyl-2-deoxy-β-D-erythro-pentofuranosyl)-2-chloro-6-O-(4-methylbenzenesulfonyl)purine(3′b). Treatment of 2′b (1.45 g, 2.3 mmol) by method 2 gave 3′b (1.30 g,87%) as a slightly yellow foam with UV max 267 nm, min 255 nm; ¹H NMR(DMSO-d₆) δ 2.45 (s, 3H), 2.86 (ddd, J=3.4, 6.2, 14.0 Hz, 1H), 3.21-3.30(“quint”, J=7.0 Hz, 1H), 4.55-4.67 (m, 3H), 5.82-5.84 (m, 1H), 6.56-6.61(m, 1H), 7.42-7.72 (m, 8H), 7.88 (d, J=7.8 Hz, 2H), 8.04-8.07 (m, 4H),8.88 (s, 1H); HRMS m/z671.0983 (MNa⁺ [C₃₁H₂₅ClN₄O₈SNa]=671.0979.

Example 7

Preparation of9-(3,5-Di-O-acetyl-2-deoxy-β-D-erythro-pentofuranosyl)-2-amino-6-chloropurine(5a). Method 3. A mixture of 1a (540 mg,, 1.54 mmol), BTEA-Cl (710 mg,3.1 mmol), N,N-dimethylaniline (215 μL, 206 mg, 1.7 mmol), and POCl₃(720 μL, 1.2 g, 7.7 mmol) in MeCN (6 mL) was stirred in a preheated oilbath (85° C.) for 10 min. Volatiles were flash evaporated immediately(in vacuo), and the yellow foam was dissolved (CHCl₃, 15 mL) and stirredvigorously with crushed ice for 15 min. The layers were separated, andthe aqueous phase was extracted (CHCl₃, 3×5 mL). Crushed ice wasfrequently added to the combined organic phase, which was washed[(ice-H₂O (3×5 mL), 5% NaHCO₃/H₂O (to pH ˜7)] and dried (MgSO₄).Volatiles were evaporated, and the residue was chromatographed(CH₂Cl₂/MeOH) to give 5a^(36,38) (517 mg, 90%) as a white solid foamwith UV max 248, 310 nm, min 268 nm; ¹H NMR (500 MHz, DMSO-d₆) δ 2.02(s, 3H), 2.08 (s, 3H), 2.49-2.52 (m, 1H), 3.04-3.06 (m, 1H), 4.20-4.29(m, 3H), 5.32-5.34 (“d”, 1H), 6.23-6.26 (m, 1H); 7.03 (br s, 2H), 8.35(s, 1H); ¹H NMR δ 2.03 (s, 3H), 2.08 (s, 3H), 2.51 (ddd, J=2.7, 5.9,14.2 Hz, 1H), 2.85-2.94 (“quint”, J=7.1 Hz, 1H), 4.28-4.42 (m, 3H),5.35-5.37 (m, 1H), 6.21-6.26 (m, 1H), 7.89 (s, 1H); HRMS (El) m/z369.0844 (M⁺ [C₁₄H₁₆ClN₅O₅]=369.0840).

Example 8

Preparation of2-Amino-9-(3,5-di-O-benzoyl-2-deoxy-β-D-erythro-pentofuranosyl)-6-chloropurine(5b). Treatment of 1b (2.38 g, 5 mmol) by method 3 gave 5b (2.10 g, 85%)as a slightly yellow solid foam with UV max 310 nm; ¹H NMR (DMSO-d₆) δ2.69-2.78 (“ddd”, 1H), 3.20-3.24 (“quint”, J=7.2 Hz, 1H), 4.56-4.67 (m,3H), 5.77-5.79 (“d”, 1H), 6.39-6.44 (m, 1H), 7.02 (br s, 2H), 7.48-7.71(m, 6H), 7.96 (d, J=8.4 Hz, 2H), 8.06 (d, J=8.7 Hz, 2H), 8.37 (s, 1H);LRMS m/z 494 (MH⁺ [C₂₄H₂₁ClN₅O₅]=494); HRMS m/z516.1042 (MNa⁺[C₂₄H₂₀ClN₅O₅Na]=516.1051).

Example 9

Preparation of9-(3,5-Di-O-acetyl-2-deoxy-β-D-erythro-pentofuranosyl)-2,6-dichloropurine(6a). Treatment of 5a (265 mg, 0.7 mmol) by method 2 gave 6a³⁹ (266 mg,95%) as a white solid foam with UV max 274 nm, min 232 nm; ¹H NMR (500MHz) δ 2.12 (s, 3H), 2.15 (s, 3H), 2.73 (dddd, J=2.4, 5.9, 14.2 Hz, 1H),2.83-2.86 (m, 1H), 4.38-4.39 (m, 3H), 5.41-5.42 (“d”, 1H), 6.45-6.50 (m,1H), 8.33 (s, 1H); HRMS m/z 411.0230 (MNa⁺ [C₁₄H₁₄Cl₂N₄O ₅Na]=411.0239).

Example 10

Preparation of9-(3,5-Di-O-benzoyl-2-deoxy-β-D-erythro-pentofuranosyl)-2,6-dichloropurine(6b). Treatment of 5b (407 mg, 0.8 mmol) by method 2 gave 6b (386 mg,91%) as a slightly yellow solid foam with UV max 274 nm, min 257 nm; ¹HNMR (500 MHz, DMSO-d₆) δ 2.87 (ddd, J=3.5, 8.0, 17.5 Hz, 1H), 3.25-3.31(m, 1H), 4.57-4.71 (m, 3H), 5.83-5.85 (“d”, 1H), 6.59-6.62 (m, 1H),7.46-7.72 (m, 6H), 7.91 (d, J=7.5 Hz, 2H), 8.09 (d, J=7.5 Hz, 2H), 8.96(s,1H); HRMS m/z 535.0562 (MNa⁺ [C₂₄H₁₈Cl₂N₄O₅Na]=535.0552).

Example 11

Preparation of 2-Chloro-2′-deoxyadenosine (Cladribine, 4). Method 4.NH₃/MeOH (12 mL, saturated at 0° C.) was added to a solution of 3a (159mg, 0.25 mmol) in CH₂Cl₂ (8 mL) in a pressure tube. The tube was sealedand immediately immersed in an oil bath preheated to 80° C. Heating (80°C.) was continued for 7 h, and volatiles were evaporated. The residuewas dissolved (H₂O, 2 mL), and the solution was applied to a column ofDowex 1×2 (OH⁻, 20 mL), the flask was rinsed (H₂O, 5 mL) and applied tothe column. The column was washed (H₂O) until the pH of the eluate wasneutral, and then MeOH/H₂O (1:1) was applied. UV-absorbing fractionswere pooled, and volatiles were evaporated. EtOH (3×10 mL) was added andevaporated, and the residue was dried (in vacuo) to give 4 (58 mg, 81%).The white powder was recrystallized from MeOH to give 4 (2 crops, 84%recovery) with mp>300° C. (crystals slowly became brown at ˜220° C.), orfrom H₂O (2 crops, 72% recovery) with mp>300 ° C. (Lit. mp softening at210-215° C.,¹⁶ then dec.; >300° C.;^(18,21) 232° C.); UV, ¹H NMR, and MSdata were in agreement with published values.^(21,22) Anal. Calcd forC₁₀H₁₂ClN₅O₃: C, 42.04; H, 4.23; N, 24.51. Found: C, 41.85; H, 4.40; N,24.46.

Treatment of 3b (83%), 3′b (43%), 6a (87%), or 6b (94%) by method 4 gave4 as white, TLC homogeneous powders with identical spectral data.

Example 12

Preparation of9-(2,3,5-Tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloropurine (8).

Method A. TMS-Cl (1.14 mL, 978 mg, 9.0 mmol) was added dropwise to astirred solution of 7 (428 mg, 1.0 mmol) in CH₂Cl₂ (30 mL) under N₂.BTEA-NO₂ (714 mg, 3.0 mmol) in CH₂Cl₂ (10 mL) was added dropwise (1drop/2 sec) and the solution was stirred at ambient temperature for 30min (TLC). The solution was diluted (CH₂Cl₂, 200 mL) and washed (5%NaHCO₃/H₂O, 5×100 mL). The combined aqueous phase was extracted (CH₂Cl₂,2×100 mL), and the combined organic phase was dried (MgSO₄) andfiltered. Volatiles were evaporated, Et₂O was added to and evaporated(3×25 mL) from the yellow oil, and the residue was recrystallized (EtOH)to give 8 (373 mg, 83%) as pale-yellow crystals with mp, UV, ¹H NMR, andMS data as reported.²⁷

Method B. TMS-Cl (444, uL, 280 mg, 3.50 mmol) was added to dropwise to astirred mixture of 7 (428 mg, 1.0 mmol) and powdered NaNO₂ (345 mg, 5.0mmol) in CH₂Cl₂ (25 mL) under N₂. BTEA-NO₂ (357 mg, 1.5 mmol) in CH₂Cl₂(25 mL) was added dropwise (1 drop/sec) and the solution was stirred atambient temperature for 1 h (TLC). The mixture was cooled for 15 min andadded dropwise to a cold, vigorously stirred mixture of saturatedNaHCO₃/H₂O (200 mL)/CH₂Cl₂ (200 mL). The aqueous layer was extracted(CH₂Cl₂ 100 mL), and the combined organic phase was washed (H₂O, 100 mL)and dried MgSO₄). Volatiles were evaporated, and the yellow oil wasrecrystallized (BuOH) to give 8 (384 mg, 85%) as pale-yellow crystals.

Method C. A solution of AcCl/CH₂Cl₂ (1 M, 2.5 mL, 2.5 mmol) was added todried CH₂Cl₂ (10 mL) under N₂, and the solution was cooled for 15 min.BTEA-NO₂ (535.5 mg, 2.25 mmol) in CH₂Cl₂ (5 mL) was then added dropwise(1 drop/2 sec) to the cold, stirred solution of AcCl/CH₂Cl₂. A coldsolution of 7 (214 mg., 0.5 mmol) in dried CH₂Cl₂ (5 mL) was then addeddropwise to the cooled, stirred AcCl/BETA-NO₂Cl₂ solution (TLC,hexanes/EtOAc, 3:7). Immediate workup and recrystallization (as inmethod B) gave 8 (187 mg, 84%) as pale-yellow crystals.

Endnotes:

¹ (a) Carson, D. A.; Wasson, D. B.; Kaye, J.; Ullman, B.; Martin, D. W.,Jr.; Robins, R. K.; Montgomery, J. A. Proc. Natl. Acad. Sci. USA 1980,77, 6865-6869. (b) Carson, D. A.; Wasson, D. B.; Taetle, R.; Yu, A.Blood 1983, 62, 737-743.

² Piro, L. D., Carrera, C. J.; Carson, D. A.; Beutler, E. N. Engl. J.Med. 1990, 322, 1117-1121.

³ Jehn, U.; Bartl, R.; Dietzfelbinger, H.; Vehling-Kaiser, U.;Wolf-Hornung, B.; Hill, W.; Heinemann, V. Ann. Hematol. 1999, 78,139-144.

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1. A method for producing 2-chloro-2′-deoxyadenosine comprising thesteps of: (a) converting the 6-oxo group of a compound having theformula

into a 6-(substituted oxy) group having sufficient reactivity in anS_(N)Ar displacement reaction; wherein R is a protecting group; (b)replacing the 2-amino group with a 2-chloro group by adiazotization/chloro-dediazoniation reaction; (c) replacing the6-(substituted oxy) leaving group with a 6-amino group; and (d) removingthe R protecting groups, to produce 2-chloro-2′-deoxyadenosine.
 2. Themethod according to claim 1, wherein the 6-(substituted oxy) group isselected from (alkyl, substituted alkyl, cycloalkyl, aryl, orsubstituted aryl)-sulfonyl, -phosphoryl, and -phosphonyl.
 3. The methodaccording to claim 1, wherein the R protecting groups are selected fromacyl and silyl.
 4. The method according to claim 1, wherein the Rprotecting groups are selected from acetyl and benzoyl.
 5. A method forproducing 2-chloro-2′-deoxyadenosine comprising the steps of: (a)reacting the 6-oxo group of a compound having the formula

with reagents selected from the group consisting of (alkyl, substitutedalkyl, cycloalkyl, aryl or substituted aryl)-sulfonyl, -phosphoryl or-phosphonyl reagents to produce a 6-O-(alkyl, substituted alkyl,cycloalkyl, aryl, or substituted aryl)-sulfonyl, -phosphoryl or-phosphonyl group that is capable of hindering nucleophilic attack atthe sulphonyl sulfur, or phosphoryl or phosphonyl phosphorous andpromoting nucleophilic attack at C6 upon subsequent ammonolysis; whereinR is a protecting group; (b) reacting the product of step (a) with ahalide source and a nitrite source in a solvent compatible with thehalide source to replace the 2-amino group with a 2-chloro group; (c)reacting the product of step (b) with a nitrogen source in a solventcompatible with the nitrogen source to replace the 6-O-(alkyl,substituted alkyl, cycloalkyl, aryl, or substituted aryl)-sulfonyl,-phosphoryl or -phosphonyl group with a 6-amino group; and (d) reactingthe product of step (b) or step (c) with a nitrogen source in a solventcompatible with the nitrogen source to remove the R protecting groups,to produce 2-chloro-2′-deoxyadenosine.
 6. A method for producing2-chloro-2′-deoxyadenosine comprising the steps of: (a) reacting the6-oxo group of a compound having the formula

with a halogen compound, to produce a 6-halo leaving group; wherein R isa protecting group; (b) reacting the product of step (a) with a halidesource and a nitrite source in a solvent compatible with the halidesource to replace the 2-amino group with a 2-chloro group; (c) reactingthe product of step (b) with a nitrogen source in a solvent compatiblewith the nitrogen source to replace the 6-halo leaving group with a6-amino group by selective ammonolysis of the 6-leaving group; and (d)reacting the product of steps (b) or (c) with a nitrogen source in asolvent compatible with the nitrogen source to remove the R protectinggroups, to produce 2-chloro-2′-deoxyadenosine.
 7. A method for producing2-chloro-2′-deoxyadenosine comprising the steps of: (a) converting the6-oxo group of a compound having the formula

into a 6-leaving group having lesser reactivity than that of the 2-aminogroup in a diazotization/chloro-dediazoniation displacement reaction;wherein R is a protecting group selected from the group consisting ofacetyl and benzoyl; (b) replacing the 2-amino group with a 2-chlorogroup by diazotization/chloro-dediazoniation of the 2-amino group; (c)replacing the 6-leaving group with a 6-amino group by selectiveammonolysis of the 6-leaving group; and (d) removing the R protectinggroups by deacylation, to produce 2-chloro-2′-deoxyadenosine.
 8. Amethod for producing 2-chloro-2′-deoxyadenosine comprising the steps of:(a) reacting the 6-oxo group of a compound having the formula

with an (alkyl, substituted alkyl, cycloalkyl, aryl, or substitutedaryl)-sulfonyl -phosphoryl, or -phosphoneyl reagent to convert the 6-oxogroup to a 6-O-(alkyl, substituted alkyl, cycloalkyl, aryl, orsubstituted aryl)-sulfonyl, -phosphoryl, or -phosphonyl group; wherein Ris a protecting group selected from the group consisting of acyl andsilyl; (b) reacting the product of step (a) with a halide source and anitrite source in a solvent compatible with the halide to replace the2-amino group with a 2-chloro group bydiazotization/chloro-dediazoniation of the 2-amino group; (c) reactingthe product of step (b) with ammonia in a compatible solvent, or with anitrogen source capable of being converted to an amino group in asolvent compatible with the nitrogen source, to replace the 6-O-(alkyl,substituted alkyl, cycloalkyl, aryl, or substituted aryl)-sulfonyl,-phosphoryl, and -phosphonyl group with a 6-amino group; and (d)reacting the product of step (c) with a suitable reagent in a compatiblesolvent to remove the R protecting groups, wherein the suitable reagentis a basic reagent when R is acyl and an acidic reagent or fluoridesource when R is silyl, to produce 2-chloro-2′-deoxyadenosine.
 9. Amethod for producing 2-chloro-2′-deoxyadenosine comprising the steps of:(a) reacting the 6-oxo group of a compound having the formula

with a halogen reagent selected from the group consisting of metalchlorides, metal chloride salts, acyl chlorides, sulfonyl chlorides,silyl chlorides, and alkyl and aryl substituted ammonium chloride salts,to convert the 6-oxo group to a 6-chloro group; wherein R is aprotecting group selected from the group consisting of acyl and silyl;(b) reacting the product of step (a) with a halide and an organicnitrite in a solvent compatible with the halide to replace the 2-aminogroup with a 2-chloro group by diazotization/chloro-dediazoniation ofthe 2-amino group; (c) reacting the product of step (b) with ammonia ina compatible solvent, or with a nitrogen source capable of beingconverted to an amino group in a solvent compatible with the nitrogensource, to replace the 6-chloro group with a 6-amino group; and (d)reacting the product of step (c) with a suitable reagent in a compatiblesolvent to remove the R protecting groups, wherein the suitable reagentis a basic reagent when R is acyl and an acidic reagent or a fluoridesource when R is silyl, to produce 2-chloro-2′-deoxyadenosine.